Drug discovery often involves assays, that determine the activity of potential drug candidate against specific biological materials, including cells, cellular components, and biomimetic analogs. Such assays are often performed in the presence of a panel of molecules. Where an assayed molecule modulates these specific biological or biomimetic materials in a desirable fashion, this molecule can then undergo further, more specific testing for use as a pharmaceutical preparation or can be chemically or biologically modified to augment its activity. The modified molecule that exhibits the best profile of beneficial activity is then formulated as a drug for the treatment of the targeted pathological process.
One can assay the activity of tens of thousands of molecules simultaneously when using high-throughput screening (HTS) techniques. Where molecules can only be synthesized one at a time, the rate of molecule submission to an assay becomes a debilitating, limiting factor. This problem has led researchers to develop methods by which large numbers of molecules possessing diverse chemical structures can be rapidly and efficiently synthesized. One such method is the construction of chemical combinatorial libraries.
Chemical combinatorial libraries are diverse collections of molecular compounds. Gordon et al. (1995) Acc. Chem. Res. 29:144–154. These compounds are formed using a multistep synthetic route, wherein a series of different chemical modules can be inserted at any particular step in the route. By performing the synthetic route multiple times in parallel, each possible permutation of the chemical modules can be constructed. The result is the rapid synthesis of hundreds, thousands, or even millions of different structures within a chemical class.
The initial work in combinatorial library construction focused on peptide synthesis. Furka et al. (1991) Int. J Peptide Protein Res. 37:487–493; Houghton et al. (1985) Proc. Natl. Acad. Sci. USA 82:5131–5135; Geysen et al. (1984) Proc. Natl. Acad. Sci. USA 81:3998–4002; and Fodor et al. (1991) Science 251:767.
Polycarbamate and N-substituted glycine libraries have been synthesized containing chemical entities that are similar to peptides in structure, but possess enhanced proteolytic stability, absorption and pharmacokinetic properties. Cho et al. (1993) Science 261:1303–1305; Simon et al. (1992) Proc. Natl. Acad. Sci. USA 89:9367–9371. Furthermore, benzodiazepine, pyrrolidine, and diketopiperazine libraries have been synthesized. Bunin et al. (1992) J. Am. Chem. Soc. 114:10997–10998; Murphy et al. (1995) J. Am. Chem. Soc. 117:7029–7030; and Gordon et al. (1995) Biorg. Medicinal Chem. Lett. 5:47–50. Oligosaccharides have also been synthesized on solid support. P. H. Seeberger, S. J. Danishefsky, Acc. Chem. Res., 31 (1998), 685. However, a need exists to develop new combinatorial libraries, particularly those that are difficult to prepare using traditional synthetic chemistry.